title: Cooperativity within and among Pten, p53, and Rb pathways induces high-grade astrocytoma in adult brain.
abstract: Mutations in the PTEN, TP53, and RB1 pathways are obligate events in the pathogenesis of human glioblastomas. We induced various combinations of deletions in these tumor suppressors in astrocytes and neural precursors in mature mice, resulting in astrocytomas ranging from grade III to grade IV (glioblastoma). There was selection for mutation of multiple genes within a pathway, shown by somatic amplifications of genes in the PI3K or Rb pathway in tumors in which Pten or Rb deletion was an initiating event. Despite multiple mutations within PI3K and Rb pathways, elevated Mapk activation was not consistent. Gene expression profiling revealed striking similarities to subclasses of human diffuse astrocytoma. Astrocytomas were found within and outside of proliferative niches in the adult brain.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Lionel M L
authors.initials: LM
authors.lastname: Chow
authors.forename: Raelene
authors.initials: R
authors.lastname: Endersby
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhu
authors.forename: Sherri
authors.initials: S
authors.lastname: Rankin
authors.forename: Chunxu
authors.initials: C
authors.lastname: Qu
authors.forename: Junyuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Alberto
authors.initials: A
authors.lastname: Broniscer
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Baker
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D020794:Receptor Protein-Tyrosine Kinases; D051059:PTEN Phosphohydrolase